Inherited metabolic disorders (IMD) are variably expressive, complicating identification of affected individuals. A genotype-first approach can identify individuals at risk for morbidity and mortality from undiagnosed IMD and lead to protocols that improve clinical detection, counseling, and management. Using data from 57,340 participants in two hospital biobanks, we assessed the frequency and phenotypes of individuals with pathogenic/likely pathogenic variants (PLPV) in two IMD genes: GLA, associated with Fabry disease and OTC, associated with ornithine transcarbamylase deficiency. Approximately 1 in 19,100 participants harbored undiagnosed PLPVs in GLA or OTC. We identified three individuals (2 male, 1 female) with PLPV in GLA, all of whom were undiagnosed, and three individuals (3 female) with PLPV in OTC, two of whom were undiagnosed. All three individuals with PLPV in GLA (100%) had symptoms suggestive of mild Fabry disease and one individual (14.2%) had an ischemic stroke at age 33, likely indicating the presence of classic disease. No individuals with PLPV in OTC had documented hyperammonemia despite exposure to catabolic states, but all (100%) had chronic symptoms suggestive of attenuated disease, including mood disorders and migraines. In this study, we identified undiagnosed adults with PLPV associated with IMD whose phenotypes ranged from attenuated to classic disease. Our findings suggest that GLA and OTC variants identified via a genotype-first approach are of high penetrance and that population screening of these genes can be used to facilitate stepwise phenotyping and appropriate care.